The design and identification of brain penetrant inhibitors of phosphoinositide 3-kinase α

  • J Med Chem. 2012 Sep 27;55(18):8007-20. doi: 10.1021/jm300867c.
Timothy P Heffron  1 ,  Laurent Salphati ,  Bruno Alicke ,  Jonathan Cheong ,  Jennafer Dotson ,  Kyle Edgar ,  Richard Goldsmith ,  Stephen E Gould ,  Leslie B Lee ,  John D Lesnick ,  Cristina Lewis ,  Chudi Ndubaku ,  Jim Nonomiya ,  Alan G Olivero ,  Jodie Pang ,  Emile G Plise ,  Steve Sideris ,  Sean Trapp ,  Jeffrey Wallin ,  Lan Wang ,  Xiaolin Zhang
Affiliations
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. [email protected]
PMID: 22946614 DOI: 10.1021/jm300867c
Abstract

Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kα has received significant attention for its potential in Cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many Cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, we report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. We leveraged our historical experience with PI3K inhibitors to identify correlations between physicochemical properties and transporter efflux as well as metabolic stability to focus the selection of molecules for further study.